Type 4 (hyperkalemic) renal tubular acidosis

Hypoaldosteronism and hypoadrenalism cause a metabolic acidosis by causing a renal loss of sodium by interfering with the ENaC channel, as well as by impairing renal ammoniagenesis and decreasing chloride secretion.

Type 4 renal tubular acidosis is an entity which can result from an interruption of the actions of aldosterone at any stage, as well as from mutations in the regulatory proteins  which regulate the function of sodium potassium and chloride resorption (and which manifest as a series of rare Mendelian disorders).

The influence of aldosterone on renal handling of sodium chloride and potassium

The distal convoluted tubule contains the thiazide-sensitive sodium-chloride cotransporter, which is actually an aldosterone-activated protein. This plays a major role in transporting both sodium and chloride out of the lumen; its action is neutral in terms of strong ion difference (as both an anion and a cation are returned to the body fluids).

Another well known major player in sodium handling is the aldosterone-responsive epithelial sodium channel (ENaC). Typically, in the presence of aldosterone, this channel opens to allow sodium reabsorption in the principal cells of the cortical collecting duct, thereby returning a strong cation to the body fluids.

The extraction of sodium from the lumen allows the excretion of potassium into the lumen by the ROMK channel, in a tit-for-tat exchange of cations. Again, this all happens in the principal cell, and both the ENaC and ROMK activity is regulated by aldosterone receptors.

Mechanism of type 4 renal tubular acidosis

There are several mechanisms of hyperkalemia and metabolic acidosis in this heterogenous group of disorders. The major roles in the pathogenesis are played by a decrease in renal ammonia excretion and by the increase in paracellular chloride reabsorption which results from this.

The role of hyperkalemia in the impairment of renal ammonia clearance
In the classical literature, much is made of the degree to which renal ammoniagenesis is impaired by hyperkalemia, and how this decreases H+ excretion. Of course, the relevance of H+ and NH3 excretion is minimal – after all, fresh water is a near-infinite source of H+ ions. The whole point of excreting NH4+ is to have a weak cation to excrete together with chloride, so that one does not waste one’s sodium and potassium.

Now, the impairment of renal ammoniagenesis can be viewed in terms of its influence on chloride excretion. The consequence of low urinary ammonia is chloride retention, and a decreasing strong ion difference. This decrease in the rate of ammonia generation has been attributed to hyperkalemia. This can be demonstrated, at least in rats. The major defect seems to be due to the impaired medullary ability to concentrate ammonium in its interstitial fluids. Remember that ammonium excreted in the proximal tubule is reabsorbed in the thick ascending limb as a part of a countercurrent multiplication mechanism which concentrates ammonia in the renal medulla. The highly concentrated ammonia is then excreted  into the medullary collecting ducts. It has been shown that hyperkalemia interferes with the mechanism of ammonia concentration by interfering with the reabsorption of ammonium at the thick ascending limb. The job of reabsorbing ammonium belongs to the famously frusemide-related Na+/K+/2Cl- cotransporter, for the services of which potassium and ammonia compete. 

So; the decrease in ammonia reabsorption leads to decreased ammonia concentration and thus to diminished ammonia levels in the lumen of the distal convoluted tubule. This is the last series of gap junctions which are permeable to chloride (as it is known that cortical collecting duct gap junctions are pretty tightly shut to everything, chloride included). Diminished ammonia levels here echo diminished chloride levels. There is no chloride excretion without ammonium excretion.

Further downstream, in the cortical collecting duct, paracellular transport of chloride is now impossible. Under normal conditions, the actions of the ENaC channel would result in reabsorption of sodium here. Likewise, the ROMK potassium channel would excrete potassium into the lumen.

Now, let us consider what may happen if aldosterone receptors are not being activated. Sodium extraction from the tubular lumen would be greatly decreased; thus potassium secretion would be greatly decreased because the driving electric potential difference is gone. Potassium stays in, and sodium stays out, which is essentially a single-phrase description of the electrolyte abnormalities in hypoaldosteronism.

Lastly, whatever chloride is present in the lumen of the cortical collecting duct becomes exposed to the activity of the chloride-bicarbonate kAE1 exchanger, which can increase the chloride retention even further (in a similar fashion to its role in the pathogenesis of type 1 (distal) renal tubular acidosis).

In this fashion, one can summarise by saying that type 4 tubular acidosis is a condition where multiple mechanisms  conspire to decrease the renal capacity for chloride excretion, by interfering with the excretion of ammonium.

Causes of type 4 renal tubular acidosis

They are legion. Just see this confusing diagram:

Failure of renin secretion due to inhibited synthesis

• Diabetes and diabetic nephropathy – by decreasing the conversion of prorenin to renin
• NSAIDs by decreasing renin secretion (by some sort of prostaglandin-inhibition-related effect)

Failure of renin secretion due to destruction of juxtaglomerular cells

• Glomerulonephritis
• NSAID-related interstitial nephritis
• Diabetic nephropathy

One may have a defect of renin secretion, giving rise to a decreased aldosterone secretion.. Given that the juxtaglomerular cells secrete this, one can assume that some sort of catastrophic damage to the glomerulus would result in a dimiished secretion of renin. This may happen acutely, as with acute glomerulonephritis or NSAID-induced interstitial nephritis, or chronically, as with diabetic nephropathy.

ACE-inhibitors and  Angiotensin-2 receptor blockers
These first-line heart failure drugs are probably responsible for a massive proportion of unrecognised type 4 RTA.
As these block the actions of angiotensin-2, the release of aldosterone is also inhibited. Though this seems to happen in up to 10% iof outpatients, it seems one needs to have some risk factors in order for it to become a problem. Weirdly, heparin can block the angiotensin-2 receptors – specifically in the aldosterone-secreting zona glomerulosa. It seems that with prolonged heparin use the zona glomerulosa can actually atrophy.

Decreased aldosterone secretion

• Primary hypoaldosteronism or primary adrenal insufficiency
• Secondary hypoaldosteronism (due to suppression by exogenous steroids)
• NSAIDs
• Critical illness (because the crisis-related oversecretion of ACTH cause the adrenal glands to divert their synthetic function to the production of cortisol, forgetting all about aldosterone)

Aldosterone receptor malfunction

• Calcineurin inhibitors, eg. tacrolimus and cyclosporine
• Spironolactone and eplrenone

ENaC sodim channel blockade

• Amiloride, triamterene
• Trimethoprim

Management of type 4 renal tubular acidosis

This, in spite of the many causes, is reasonably simple.
If the patient has been intoxicated with a drug which it is feasible to cease, one expends little intellectual energy in ceasing that drug. If, however, the drug cannot be ceased, or there is a non-drug-related aetiology, one may supplement the patients’ aldosterone stores with a synthetic mineralocorticoid such as fludrocortisone.